The purpose of this project is to utilize current experimental data to construct a relevant comparative structural model of the serotonin transporter (SERT) based on a recently crystallized bacterial family member. Recent advancements in computation protein folding have legitimized its use in modeling integral membrane proteins. The principal investigator, who has obtained a strong background in the study of structural aspects of SERT using biochemistry and pharmacology in the laboratory of Dr. Randy Blakely who has an outstanding research record in this area, will pursue training in the area of computational biology with a talented researcher, Dr. Jens Meiler, who has played an intergral role in development of methods to analyze protein-small molecule interaction in silico. This project with its heavy emphasis on computational modeling represents a new direction in research for the P.I. who to date has focused on molecular/biochemical study of membrane proteins. Vanderbilt University offers a superior environment for computational studies through the NIH supported ACCRE processor cluster and multiple genes formally expressed in membrane protein modeling (Lybrand, Chazin). This training will allow Dr. Henry to build, test and refine models of SERT interactions with its substrate serotonin and the club drug MDMA. These studies have the potential to provide significant insight into the structural components necessary for recognition and movement of sertonin and drugs of abuse through the transporter. Furthermore, this training will allow Dr. Henry to apply these methods to future projects and broaden his knowledge base as an academic instructor/investigator. Relevance: The serotonin transporter is arguably the most clinically relevant protein today. It is the major target of antidepressants and several drugs of abuse and has been linked to several psychological disorders including: depression, obsessive-compulsive disorder, post-traumatic stress disorder and more recently to aspects of autism. However, we still do not understand many of the details of how SERT recognizes and moves substrates like serotonin and MDMA into the nerve cell. Understanding these aspects of such an important process in the nervous system could have an important impact on clinical targeting of SERT as well as the related norepinepherine and dopamine transporters all which play critical roles in our neurological and psychological health.